A multi-institutional group seeks to renew funding of a very successful ongoing collaboration that has already identified a clinical candidate for treating HIV-1 infection, i.e., U-87201E, a nonnucleoside inhibitor of the HIV-1 reverse transcriptase (RT). This proposal contains 4 projects that represent an integrated, rational plan to identify, evaluate, and optimize novel inhibitors of HIV replication. Four of the project at Upjohn Laboratories will principally seek to identify and optimize the antiviral and pharmaceutical properties of inhibitors of the essential ribonuclease H (RNase H) activity of the HIV RT. These projects will integrate with one another and use a "Structure- Driven Drug Design Paradigm" to develop lead inhibitors into drug candidates. Studies investigating RT subunit interaction as it relates to the control of reverse transcription will be performed. Work on new classes of RT inhibitors already identified in the Upjohn chemical inventory will be evaluated for novel mechanisms of inhibiting the HIV RT. Together these projects represent a group of research talents not attainable at any single institution. The experience of this group and their documented productivity in the AIDS research area, insure this program will continue to be successful.